Pergolide 1 (D-6-n-propyl-8β-methylmercaptomethylergoline) is a semisynthetic ergot alkaloid (produced by a fungus of genus Claviceps, Claviceps purpurea) used for the therapy of Parkinson's disease.
In particular, pergolide mesylate 2, a strong agonist of dopaminergic receptors, is used in therapy. 
The usual starting product for the synthesis of pergolide is lysergic acid 3 (D-6-methyl-8β-carboxy-9-ergolene), which can be obtained by fermentation. 
U.S. Pat. No. 4,166,182 discloses a synthesis of pergolide (scheme 1) which comprises conversion of lysergic acid into D-6-n-propyl-8β-hydroxymethylergoline 4, derivatization of the hydroxy group with methanesulfonyl chloride and reaction with sodium thiomethoxide. The resulting pergolide can then be salified with methanesulfonic acid. 
Compound 4 is obtained (scheme 2) by catalytic reduction of lysergic acid 3 to 9,10-dihydrolysergic acid 6, esterification of the acidic function and reduction of ester 7 with NaBH4. The resulting compound 8, known as dihydrolysergol or 8,9-dihydroelimoclavine, is demethylated at the nitrogen in position 6 (following, for example, the procedure disclosed in U.S. Pat. No. 3,901,894 or the procedure disclosed in J. Pharm. Sci. 1981, 70, 1319–21), to give D-8β-hydroxymethylergoline 9, which is alkylated, for example, with propyl iodide in the presence of bases.
The key-intermediate of this pathway, dihydrolysergol 8, can also be obtained from elimoclavine, another fermentation product of Claviceps purpurea, by means of catalytic reduction, according to U.S. Pat. No. 3,901,894. 
Alternatively, compound 4 can be obtained (scheme 3) by demethylation of ester 7 (obtained as described above) and by acylating with propionyl chloride the nitrogen in position 6; the treatment of compound 11 with LiAlH4, which at the same time reduces the ester and the amidic function, affords compound 4. 
Even though these synthetic approaches allow to obtain highly pure pergolide, they require recovery of a number of intermediates, which determines poor yields (not higher than 20%) and makes the processes time-consuming and unsafe.
A more convenient synthesis in terms of yields has been disclosed by Misner in U.S. Pat. No. 5,465,060; the method allows to prepare “one-pot” pergolide from dihydrolysergol 8 (scheme 4), by demethylation of quaternary ammonium salts with nucleophiles, according to Hutchins e Duc (J. Org. Chem. 1973, 38, 1961–2). Dihydrolysergol 8 is transformed into an intermediate quaternary ammonium salt 12 by treatment with propyl iodide, whose alcoholic hydroxy group is subsequently derivatized with methanesulfonyl chloride to give an intermediate of formula 13. The treatment with sodium thiomethoxide allows at the same time demethylation of the quaternary nitrogen and formation of the thiomethyl ether. Despite a reduced number of steps and high yields (above 70%), the resulting pergolide is contaminated by some ergolinic impurities, which cannot be removed by conventional crystallization. For this reason two chromatographic purification steps are necessary, one of them with preparative HPLC [W. Misner et al., Org. Process Res. Dev. (1997) 1, 77–80], which require the use of highly toxic solvents, such as acetonitrile and chloroform [J. H. Kennedy, Org. Process Res. Dev. (1997) 1, 68–71] and increase the risk of exposure to the final product. 